Link: https://www.ncbi.nlm.nih.gov/pubmed/30532227

PLoS Genet. 2018 Dec 10;14(12)007822. doi: 10.1371/journal.pgen.1007822. [Epub ahead of print]
De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.
Qi H1,2, Yu L3, Zhou X1,3, Wynn J3, Zhao H1,4, Guo Y1, Zhu N1,3, Kitaygorodsky A1,4, Hernan R3, Aspelund G5, Lim FY6, Crombleholme T6, Cusick R7, Azarow K8, Danko ME9, Chung D9, Warner BW10, Mychaliska GB11, Potoka D12, Wagner AJ13, ElFiky M14, Wilson JM15,16, Nickerson D17, Bamshad M17, High FA15,16,18, Longoni M16,18, Donahoe PK16,18, Chung WK3,19,20, Shen Y1,4,21.
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Abstract
Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10-, including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.

PMID: 30532227 DOI: 10.1371/journal.pgen.1007822